1. Field of the Invention
The present invention relates to new compounds used as medicines for improving symptoms caused by thromboxane. Moreover, this invention relates to compounds as represented by the general formula (I) and their salts, which are used as antithrombotic, anti-vasoconstricting, and anti-bronchoconstricting drugs. ##STR2## wherein R.sub.1 is hydrogen or lower alkyl; R.sub.2 is alkyl, substituted or unsubstituted aryl, aralkyl or heterocycle; R.sub.3 is hydrogen or methyl; X is alkylene or alkenylene which may be substituted by a fluorine atom or atoms and may contain an oxygen, sulfur and/or phenylene in the chain; Y is straight or branched alkylene or alkenylene, oxygen, or sulfur; m indicates 0 or 1; and n indicates 0, 1 or 2, or its salt.
In detail, the compounds of this invention can be represented by the following general formulae. ##STR3## wherein R.sub.1, R.sub.2, R.sub.3, X and Y each is as defined above.
In more detail, the compounds of this invention can be represented by the following general formulae (Ia) to (Ih). ##STR4## wherein R.sub.1 R.sub.2 and X each is as defined above.
When thrombin acts on platelets, cyclooxygenase is activated. By activation of cyclooxygenase, thromboxane A.sub.2 is produced enzymatically in platelets, vessel wall, and various other cells, from arachidonic acid through prostaglandins G.sub.2 and H.sub.2. This product has various potent physiologic or pathogenic actions. In particular, the potent platelet agglutination action and the action constricting the smooth muscle of bronchi, and of coronary, cerebral and pulmonary arteries, etc. are considered to be the factors which relate to the onset and progress of such circulatory and respiratory diseases as angina pectoris, myocardial infarction, cerebral infarction, and bronchial asthma. Moreover, it is said that the strong action occurs even at a concentration of 10.sup.-10 -10.sup.-11 M. Therefore, increasing attention has been paid to the development of thromboxane A.sub.2 antagonists or inhibitors as anti-thrombotics, anti-vasoconstrictives or anti-bronchoconstrictives. Inhibitors, however, have some problems: in view of the fact that they influence on prostaglandins which bear various important roles as well as thromboxane A.sub.2, and uncontrollable thromboxane-like harmful effects are caused by accumulated substrates such as prostaglandins H.sub.2. So, development of antagonists has especially been sought.
The inventors succeeded in the synthesis of the bicyclic sulfonamide derivatives represented by the general formula (I), and found that these new compounds have potent activity as thromboxane A.sub.2 receptor antagonists, and are chemically and biochemically stable. The present invention was based on these findings.
2. Description of the Prior Art
The general course of atherosclerosis, which is regarded as the main risk factor of myocardial infarction and cerebral infarct, begins in the arterial intima with mucoid accumulation and fibroblast formation, progressively followed by degeneration, lipid and cholesterol deposition, and destruction and atheromasia of the intima tissue, with gradual formation of high-degree and localized hypertrophy in the intima. The atherosclerosis has long been regarded to be caused by thrombuse formation and fibrin deposition, but recent discoveries of thromboxane A.sub.2 (TXA.sub.2) by Samuelsson et al. and prostacyclin (PGI.sub.2) by Vane et al. have revealed an interaction between platelets and vessel wall. Platelets are said to play an important role in the onset and progress of atherosclerosis. Therefore, it is now recognized that the use of antithrombotic drugs, particularly drugs which inhibit platelet agglutination, are effective for the treatment of atherosclerotic diseases.
In addition to the conventional antithrombotic drugs such as heparin and coumarin compounds, certain types of prostaglandins are known to have a potent platelet agglutination inhibitory action. From these facts, prostaglandin derivatives have attracted much attention as possible antithrombotic drugs. For example, analogues of prostaglandin E.sub.1 and I.sub.2 receptor agonists have been developed. Since thromboxane A.sub.2 shows potent platelet agglutination and vasoconstriction action, thromboxane A.sub.2 synthesis inhibitors, such as cyclooxygenase inhibitors and thromboxane synthetase inhibitors, and thromboxane A.sub.2 receptor antagonists, have been developed. The thromboxane A.sub.2 receptor antagonists include 13-APA [Venton D. L. et al., J. Med. Chem., 22, 824 (1979)], PTA.sub.2 [Lefer A. M. et al., Proc. Natl. Acad. Sci. U.S.A., 76, 2566, (1979)], BM-13177 ]Lefer A. M. et al., Drugs of Today, 21, 283 (1985)], SQ-29548 [Ogletree et al., J. Pharmacol. Exp. Ther., 34, 435, (1985)], and the compounds as disclosed in U.S. patent application No. 259154/1985.